The present invention relates to a series of new derivatives of the known compound ML-236B, to processes for their preparation and to pharmaceutical compositions containing them.
ML-236B, which has the following chemical structure: ##STR3## is disclosed in U.S. Patent Specification No. 3,983,140. It has been isolated and purified from the metabolic products of microorganisms of the genus Penicillium, especially Penicillium citrinum, a species of blue mould. It has been shown to inhibit the biosynthesis of cholesterol by enzymes or cultured cells separated from experimental animals by competing with the rate-limiting enzyme active in the biosynthesis of cholesterol, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase and, as a result, significantly reduces serum cholesterol levels of animals [Journal of Antibiotics, 29, 1346 (1976)]. A number of compounds structurally related to ML-236B have also been discovered and found to possess the ability to inhibit the biosynthesis of cholesterol.
We have now discovered a series of new compounds, which may be prepared by the enzymatic hydroxylation of ML-236B or of derivatives thereof, and which possess an ability to inhibit the biosynthesis of cholesterol which is at least comparable with, and in some instances substantially exceeds, that of ML-236B itself.